Preclinical Studies of the Potent and Selective Nicotinic α4β2 Receptor Ligand VMY-2-95

The discovery and development of small molecules that antagonize neuronal nicotinic acetylcholine receptors may provide new ligands for evaluation in models of depression or addiction. We discovered a small molecule, VMY-2-95, a nAChR ligand with picomolar affinity and high selectivity for alpha 4 beta 2 receptors. In this study, we investigated its preclinical profile in regards to solubility, lipophilicity, metabolic stability, intestinal permeability, bioavailability, and drug delivery to the rat brain. Metabolic stability of VMY-2-95 center dot 2HCl was monitored on human liver microsomes, and specific activity of VMY-2-95 center dot 2HCl on substrate metabolism by CYP1A2, 2C9, 2C19, 2D6, and 3A4 was tested in a high-throughput manner. The intestinal transport of VMY-2-95 center dot 2HCl was studied through Caco-2 cell monolayer permeability. VMY-2-95 center dot 2HCl was soluble in water and chemically stable, and the apparent partition coefficient was 0.682. VMY-2-95 center dot 2HCl showed significant inhibition of CYP2C9 and 2C19, but weak or no effect on 1A2, 2D6, and 3A4. The Caco-2 cell model studies revealed that VMY-2-95 center dot 2HCl was highly permeable with efflux ratio of 1.11. VMY-2-95 center dot 2HCl achieved a maximum serum concentration of 0.56 mg/mL at 0.9 h and was orally available with a half-life of similar to 9 h. Furthermore, VMY-2-95 center dot 2HCl was detected in the rat brain after 3 mg/kg oral administration and achieved a maximal brain tissue concentration of 2.3 mu g/g within 60 min. Overall, the results demonstrate that VMY-2-95 center dot 2HCl has good drug like properties and can penetrate the blood-brain barrier with oral administration.